tbuckley/cabot-search huggingface dataset:
Real-world use, tolerability, and dose modifications of PARP inhibitors in ovarian cancer.
Authors: David M. O'Malley, Rebecca Christian Arend, Naufil Alam, Ozan Ozgoren, Kimmie K. McLaurin, Grainne H. Long, Susana N. Banerjee
Journal: Journal of Clinical Oncology (2022)

5552 Background: Tolerability is a key consideration when selecting a PARP inhibitor (PARPi) for ovarian cancer (OC). Here we expand on earlier work (Arend et al 2021) to further characterize real-world tolerability and dose modifications in US patients (pts) with OC receiving PARPi therapy. Methods: A retrospective cohort of OC pts starting olaparib (ola), niraparib (nir) or rucaparib (ruc) between Jan 2017 and Dec 2020 was identified from MarketScan ® Commercial/Medicare Supplemental databases, increasing the period covered and number of pts included vs our previous analysis. Pts were followed up from first PARPi prescription (index) for ≥30 days until end of study period, disenrollment or death; baseline was 6 months pre-index. Clinical events of interest (CEIs; acute myeloid leukemia/myelodysplastic syndromes, anemia, leukopenia/neutropenia, thrombocytopenia, acute kidney injury, arthralgia, constipation, diarrhea, nausea, vomiting, dermatitis/rash/photosensitivity, fatigue, hypertension, infection, insomnia, pneumonitis, transaminitis) were identified via ICD-9/10 codes. Multivariable Cox regression compared the likelihood of CEIs, dose modifications and hospitalizations between PARPis, adjusting for baseline CEI, Charlson Comorbidity Index score, prior bevacizumab and cancer-related surgery. Persistence was defined as no PARPi treatment gaps of &gt;90 days in pts with ≥6 months’ continuous enrollment. Results: Overall, 637, 538 and 227 pts received ola, nir and ruc, respectively (median [IQR] follow-up 10.5 [13.4] months). Baseline characteristics were similar across groups. The proportion of pts initiating PARPi at the highest indicated dose was 89.2%, 57.6% and 89.9% for ola, nir and ruc, respectively; 22.6%, 34.8% and 28.6%, respectively, required dose decreases. The likelihood of experiencing CEIs varied across the PARPis after adjusting for a priori confounders as shown in the table. Persistence with index PARPi was higher with ola (83.4%) vs nir (73.3%; P&lt;0.001) and similar vs ruc (80.2%; P&gt;0.05). Among all pts, mean time to non-persistence was shorter with nir vs ola and ruc (6.4 vs 7.9 and 7.6 months, respectively; both P&lt;0.05). CEIs by PARPi dose and calendar year will also be presented. Conclusions: This is the largest real-world comparison of PARPi use in OC pts reported to date. It supports differences between PARPis in persistence with therapy and risk of experiencing a CEI, even after adjusting for confounders. [Table: see text]
Are pivotal clinical trials for lymphomas that led to drug approval representative of the population affected by these diseases?
Authors: Mycal Casey, Lorriane Achieng Odhiambo, Mahran Shoukier, KM Islam, Nidhi Aggarwal, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2022)

6531 Background: There are significant inequities in cancer care and outcomes in the United States (US) and worldwide. Race, ethnicity, and sex all define sub-groups affected by these inequities. Randomized controlled trials (RCTs) provide new therapies in cancer care. Many new drugs have been recently approved for the management of lymphoma. We examined whether pivotal clinical trials included populations representative of those affected. Methods: Lymphoma clinical trials were collected from the US Food and Drug Administration (FDA) Databases ‘Oncology (cancer)/Hematologic Malignancies approval notifications’ and ‘Novel Drug Approvals’ between 2011 and 2021. Trials were also reviewed for demographic data on ClinicalTrials.gov (CT.gov) and Primary Literature related to the drug approval. Only studies for adult patients were included; one study was excluded due to inconsistencies in the total patients enrolled and the totals by race. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) RCTs were not included. The burden of diseases based on Surveillance, Epidemiology, and End Results (SEER) data was used as a comparison for US participants. Results: Thirty-three pivotal trials were identified from the FDA databases (2011-2021); 18 (54.5%) had available race data on CT.gov or in Primary Literature. Three trials focused on classical Hodgkin’s Lymphoma (cHL) and 15 on Non-Hodgkin’s Lymphoma (NHL). Two of the three trials for cHL with available data for race reported ethnicity data. Only 10 of 15 NHL trials that reported race demographics had available ethnicity data. Table 1 shows trials that had available data for race and ethnicity along with proportions from the SEER data. There was underrepresentation of Blacks and to some extent Hispanics in both cHL and NHL trials. Females were also underrepresented, particularly in NHL trials. Conclusions: There is racial, ethnic, and sex misrepresentation within clinical trials that led to approval of drugs for lymphomas in the US between 2011 and 2021. In addition, there was significant underreporting of racial and ethnic subgroups noted in the clinical trials.[Table: see text]
Comparative healthcare research outcomes of novel Surgery in prostate cancer (IP4-CHRONOS): Pilot RCT assessing feasibility of randomization for focal therapy in localized prostate cancer.
Authors: Deepika Reddy, Tim Dudderidge, Taimur Shah, Stuart McCracken, Manit Arya, Francesca Fiorentino, Emily Day, Andrew Prevost, Mark Emberton, John Staffurth, Sarbjinder Sandhu, Richard Hindley, Nim Arumainayagam, Matthew R. Sydes, Vincent Khoo, Mathias Winkler, Hashim Uddin Ahmed
Journal: Journal of Clinical Oncology (2022)

5086 Background: Randomised comparative data is lacking for focal therapy in localised prostate cancer. Imperial Prostate 4 CHRONOS (IP4- CHRONOS) is an RCT designed to reflect patient and physician equipoise to maximise acceptance to randomisation. Methods: Patients and physicians could opt for CHRONOS-A or CHRONOS-B. CHRONOS-A randomised between focal therapy (HIFU/cryotherapy) and radical therapy (radiation/prostatectomy). Using a multi-arm-multistage design, CHRONOS-B randomised between focal and focal combined with neoadjuvant medication (3 months of either finasteride or bicalutamide). We report the pilot phase outcomes on feasibility of randomisation. IP4-CHRONOS had ethics committee approval and was registered (ISRCTN17796995). Results: Due to impact of COVID-19, the target for CHRONOS-A was modified from 60 to 36; 36 patients were randomised over 24 months from 7 sites (Nov/2019-Nov/2021). CHRONOS-B randomised 64 patients over 14 months across 6 sites (Dec/2019-Feb/2021). Median (IQR) age and PSA (ng/ml) for CHRONOS-A were 69 (65-72) years and 6 (5-7) and for 66 (60.5-70) years and 6 (4-7) for CHRONOS-B, respectively. 34/36 (94%) and 60/64 (94%) had ISUP Grade Group &gt; / = 2, respectively. 4/18 (22%) randomised to radical in CHRONOS-A withdrew consent; 1/22 (5%) randomised to focal withdrew. In CHRONOS-B, only 1/21 (5%) randomised to focal alone, and another randomised to focal with neoadjuvant bicalutamide withdrew. A qualitative recruitment intervention partially improved accrual to CHRONOS-A. Conclusions: IP4-CHRONOS evaluated patient and physician equipoise regarding focal therapy. Randomising between focal and radical therapy is not feasible due to strong patient preferences. A multi-arm, multi-stage RCT investigating the role of neoadjuvant agents combined with focal therapy is feasible. Clinical trial information: 17796995.
Phase II study of cladribine, idarubicin, cytarabine (CLIA) plus gilteritinib in patients (pts) with FLT3 mutated acute myeloid leukemia (AML).
Authors: Tareq Abuasab, Hagop M. Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban Bravo, Yesid Alvarado Valero, Naval Guastad Daver, Musa Yilmaz, Naveen Pemmaraju, Kelly Sharon Chien, Steven Mitchell Kornblau, Jan Andreas Burger, Nitin Jain, Rabiul Islam, Courtney Denton Dinardo, Gautam Borthakur, Elias Jabbour, Farhad Ravandi, Tapan M. Kadia
Journal: Journal of Clinical Oncology (2022)

e19036 Background: The addition of multi-kinase inhibitors of FLT3 such as midostaurin and sorafenib to chemotherapy have demonstrated improved outcomes in patients with newly diagnosed FLT3 mutated AML Gilteritinib (gilt) is a second generation FLT3 inhibitor approved for pts with relapsed/refractory (R/R) FLT3-mutated AML. We studied to the combination of gilt with the CLIA regimen in FLT3 mutated AML. Methods: Eligible pts were between 18-65 years (yrs) with FLT3-mutated AML. Induction was: Cladribine 5 mg/m2 IV on D1-5, Cytarabine 1.5-2.0 g/m2 IV on D1-5, Idarubicin 10 mg/m2 IV on D1-3 and gilt 120 mg on D1-14. Consolidation was cladribine 5 mg/m2 IV for 3d, Cytarabine 750 mg/m2 IV for 3 d, and idarubicin 8 mg/m2 IV for 2 d, with gilt 120 mg continuously during cycle two onward. A historical cohort combining sorafenib (400 mg PO BID) with idarubicin + cytarabine (1.5 g/m2) backbone was used as comparison. Results: Twenty-four pts were enrolled with a median age of 53 yrs (range, 28-63). 21 pts (88%) had FLT3-ITD, 6 pts (25%) had FLT3-D835, and 3 pts (13%) had both. Nineteen pts (79%) had diploid cytogenetics, and 4 pts (18%) had trisomy 8. The most commonly co-occurring mutations were: NPM1 (46%), ASXL1 (29%), DNMT3A (29%), TET2 (25%), and KDM6A (20%). 16 pts (67%) achieved complete remission (CR), 2 (8%) had CR with incomplete recovery (CRi), for a CR/CRi rate of 75%. 13 responding pts (54%) underwent to allogeneic SCT. The median overall survival for the entire cohort was not reached. We compared these outcomes to our historical cohort of 107 pts treated with sorafenib combined with high-dose cytarabine-based chemotherapy. Other than older age and greater anemia for the gilt, there was not significant difference in baseline characteristics between the two groups. The CR/CRi rate was similar (75% gilt vs. 71% sorafenib; P = &gt; 0.999) between the 2 cohorts; while there was a trend, there was no significant difference in OS with CLIA + Gilt (median NR vs. 17.3 months for sorafenib; P = 0.533). Conclusions: The combination of the FLT3 inhibitor gilteritinib to CLIA produced high rates of complete remission in pts diagnosed with FLT3-mutated AML. These results were similar for Sorafenib when combined with intensive chemotherapy with OS rates favoring gilteritinib. Further study of intensive chemotherapy with different FLT3 inhibitors is warranted. Clinical trial information: NCT02115295.
Ruxolitinib in chronic steroid-refractory graft-versus-host-disease.
Authors: Iuliia Kovalenko, Tabinda Saleem, Babray Laek, Rimsha Ali, Taaha Muddassir Mirza, Asmi Chattaraj, Ahsan Wahab, Asma Tamez ud din, Hafiz Qurashi, Konstantin Golubykh, Maidah Malik, Rafiullah Khan
Journal: Journal of Clinical Oncology (2022)

e19053 Background: Ruxolitinib, an elective Janus Kinase (JAK) 1/2 inhibitor, has been approved by FDA for the treatment of steroid-refractory chronic graft-versus-host-disease (SR cGVHD) after the failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. However, it remains underutilized despite promising results in the treatment of SR cGVHD. Methods: We did a comprehensive literature search across various data sets, including PubMed, Cochrane, and Embase, and presented data in ASH and ASCO. A review of the most recent data is summarized in this abstract. Results: Two retrospective cohort studies and one pilot prospective study evaluated ruxolitinib in SR cGVHD. In a retrospective cohort study by Yang et al., 36 patients with SR cGVHD treated with ruxolitinib showed complete response (CR) in 27.8% of patients with complete disappearance of cGVHD symptoms and partial response (PR) with symptom relief of 52.7% at a dose of 2.5 to 10 mg two times daily with ruxolitinib tapering one week after symptoms improvement. In the pilot prospective study by Mozo et al., 12 pediatric patients with SR cGVHD received ruxolitinib at a dose of 2.5 to 10 mg two times daily and showed CR in 8.3% of patients and PR in 82.7% of patients. Morozova et al. conducted a prospective pilot study in 20 patients with primary or secondary myelofibrosis who were treated with pre-transplant ruxolitinib 45 mg/day from ruxolitinib (45 mg) starting from seven days before transplant to 2 days before the transplant, and 15 mg from day five after transplant to day 100 after transplant along with cyclophosphamide 50 mg/kg on days three and four after transplant. PR was observed in 47.1% of patients at 6 months with the incidence of cGVHD of 20%. In Phase III trial by Zeiser et al. reported CR of 6.7% and PR of 43% in 165 patients treated with ruxolitinib at a dose of 10 mg daily for 6 cycles (28 days/cycle). The most common all-grade adverse events are listed here. Conclusions: Ruxolitinib was recently approved by FDA for the treatment of SR GVHD and should be utilized more due to its high effectiveness and tolerable safety profile.[Table: see text]
Stress keratin 17 as a novel biomarker of response in immune checkpoint blockade–treated head and neck squamous cell carcinoma.
Authors: Taja Lozar, Megan Fitzpatrick, Wei Wang, Howard Harry Bailey, Justine Yang Yang Bruce, Paul M. Harari, Paul Lambert
Journal: Journal of Clinical Oncology (2022)

3117 Background: Low response rates in immune checkpoint blockade (ICB) treated head and neck squamous cell carcinoma (HNSCC)drive a critical need for robust clinically validated biomarkers that can predict response to ICB. Stress keratin 17 (K17) is a known prognostic marker in various types of cancer, including HNSCC; however, its predictive value for ICB response has not been investigated. Preclinical studies suggest K17 suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors. Furthermore, knocking out K17 results in restored response to ICB in a HNSCC mouse model. Here, we evaluated if K17 protein expression predicts response to ICB in human HNSCC patients. Methods: We conducted a retrospective analysis of 26 HNSCC patients that received at least one cycle of pembrolizumab at the University of Wisconsin-Madison Carbone Cancer Center. Pretreatment, archival, formalin-fixed, paraffin-embeded samples were stained by immunohistochemistry using a K17 monoclonal antibody. Clinical outcomes were investigator-assessed for all patients with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Based on independent pathology review, cases were categorized into K17 high vs K17 low based on a cut-off of &gt; 5% strong cytoplasmic staining intensity of tumor cells in the invasive carcinoma component. Correlation between K17 expression and clinical outcomes was assesed using Fischer's exact test and log rank test. Results: The 26 patients included in this study were 85% male, median age 60.5 years, 74% ECOG performance status &lt; 2, with 80% having received prior chemotherapy. Primary site included oral cavity (54%), oropharynx (23%), larynx (4%), or other (19%). Seventeen tumors (65%) showed high K17 expression, and 9 tumors (35%) showed low K17 expression. Eleven patients (42%) had programmed death ligand 1 (PD-L1)+ tumors as determined by combined positive score. Six patients (23%, all K17 low) achieved clinical benefit, while 20 patients (77%, 17 K17 high and 2 K17 low) had progressive disease. High K17 expression was associated with lack of clinical benefit (p &lt; 0.001), shorter time to treatment failure (p &lt; 0.001), progression-free (p = 0.004) and overall survival (p = 0.02). PD-L1 expression by immunohistochemistry (clone 22C3) did not correlate with K17 expression or clinical outcome. Conclusions: Our findings suggest that K17 expression may predict clinical benefit from ICB in HNSCC patients, thus supporting further validation studies. [Table: see text]
A large-scale, multi-center molecular characterization of <i>MET</i> fusions in a real-world Chinese population.
Authors: Yutao Liu, Hui Xia, Junhua Zhang, Tongguo Si
Journal: Journal of Clinical Oncology (2022)

3064 Background: MET is a driver gene notable in its diversity of clinically relevant aberrations, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two, MET fusions are severely under-reported, leaving unanswered a series of fundamental questions. In this study, we addressed this knowledge gap by screening for and characterizing MET fusions in a real-world, multi-center population of Chinese cancer patients. Methods: We retrospectively included patients with solid tumors and available genome profiles acquired between August 2015 to May 2021. MET fusion-positive ( MET+) patients were subsequently selected for clinical and molecular characterization. Results: A total of 79816 patients across 27 tumor types were screened. We detected 155 putative MET fusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority of MET+ patients (92, 75.4%). Prevalence was markedly higher in liver, biliary tract cancer, and renal cancer (range 0.52%-0.60%) and lower in ovarian cancer (0.06%). A substantial proportion (48/58, 82.8%) of unique partners were reported for the first time. The fusion partners also turned out to be highly heterogeneous, with ST7, HLA-DRB1, and KIF5B as the three most common partners. Mutational landscape analysis of lung adenocarcinoma patients (n = 32) revealed high prevalence of aberrant TP53 in MET+ patients as well as EGFR L858R, L861Q and MET amplification as concurrent alterations. Conclusions: This study is, to our knowledge, currently the largest in characterizing MET fusions. Our findings warrant further clinical validation and mechanistic study that may translate into therapeutic avenues for MET fusion-positive cancer patients.
Clonal hematopoiesis in lung cancer and its impact on liquid biopsy based on targeted deep sequencing.
Authors: Xue Yang, Youyu Wang, Yingmei Li, Danni Liu, Mengqi Shao, Lei Liu, Yida Liao, Tanxiao Huang, Jing Zhang, Tianhao Mu, Shifu Chen, Gang Feng, Kegang Jia
Journal: Journal of Clinical Oncology (2022)

e20532 Background: Blood-based liquid biopsy has proved its potential in enormous clinical applications, such as cancer screening, diagnosis, treatment guidance, disease tracking and monitoring. In certain scenarios (e.g., molecular residual disease), it requires the technique to be able to detect mutation with very low frequency (0.001% ̃ 1%). The major hurdle of ultra-sensitive circulating tumor DNA sequencing is the high background noise of plasma cell-free DNA (cfDNA) and clonal hematopoiesis (CH). Here in this study, we investigated the prevalence of CH in lung cancer patients and its interference with liquid biopsy. Methods: We retrospectively analyzed cfDNA and blood cell genomic DNA (gDNA) sequencing data sets (n = 1,261) from a group of Chinese lung cancer patients. Threshold (1%) and subthreshold (0.2%) for variant allele frequency were set and compared. We focused on 23 clonal hematopoiesis genes that were selected based on previous publications. Results: CH mutations were detected in 27.68% of all the patients at the threshold and 62.01% at the subthreshold, and the detection rate increased with age. DNMT3A was the most frequently mutated CH gene, accounting for more than half of the CH mutations. The CH mutations had a higher detection rate in smokers (72%) than non-smokers (59.4%) at subthreshold. VAFs of CH mutations in cell-free DNA strongly correlated with their VAFs in gDNA (Pearson’s R = 0.92, p &lt; 2.2x10 -16 ), while tumor-derived somatic mutations didn’t have such correlation. Conclusions: Our study showed that clonal hematopoiesis is very common in lung cancer patients, especially when examining low-frequency mutations. Sequencing of gDNA at equivalent depth is very important to filter out CH mutation in cancer liquid biopsy.
The efficacy and safety of second allogeneic hematopoietic stem cell transplantation.
Authors: Selami Kocak Toprak, Ekin Kırcalı, Guldane Cengiz Seval, Sinem Civriz Bozdag, Meltem Kurt Yuksel, Pervin Topcuoglu, Onder Arslan, Muhit Ozcan, Taner Demirer, Gunhan Gurman, Meral Beksac, Osman Ilhan
Journal: Journal of Clinical Oncology (2022)

e19048 Background: Second allogeneic hematopoietic cell transplant (sAHCT) might be indicated following a graft failure or disease relapse after the first one; although it might emerge with high rates of morbidities and mortality. Currently, there is a limited number of publications on this matter in the literature, here we aimed to share our sAHCT experience from a single center. Methods: Data from 51 patients who were eligible for sAHCT between 2001 and 2021 was evaluated retrospectively. All data was obtained from the Ankara University Faculty of Medicine, Department of Hematology and Bone Marrow Transplant Unit. Results: 51 patients were included in the present study. Median age at sAHCT was 34 (18- 65) and female/ male ratio 19/ 32 (37.3% / 62.7%). The same donor from the first transplant was eligible for sAHCT for most patients (n= 46, 90.2 %). sAHCT indication was graft failure for 11 patients (21.6 %) whereas 40 (78.4 %) patient went on sAHCT for disease relapse. Patients’ diagnoses were as follows: acute myeloid leukemia (n= 26, 50.9 %), acute lymphoblastic leukemia (n=9, 17.6 %), myelodysplastic syndrome (n= 6, 11.8 %), aplastic anemia (n= 6, 11.8 %) and others (CMML, CML, biphenotypic leukemia). Median number of transplanted CD34+ hematopoietic cells was 5.77 x x10 6 / kg (1.11- 8.29). Stem cell source was either bone marrow (n= 5, 9.8%) or peripheral blood (n= 46, 90.2 %). Myeloablative conditioning regimens were used for most sAHCTs (n= 30, 58.8%). Median overall survival (OS) rates for graft failure and disease relapse groups were 12.8 and 18.7 months, respectively (p= 0.63). During early transplant phase, 20 patients (39.2 %) died due to bone marrow aplasia, transplant failure or other complications. 1 year OS of the entire cohort was 33.3 % whereas 2-y- OS was 21.6% (95% CI= 25-45). 2 patients (3.9 %) died due to COVID19 during transplant process. On univariate analysis, sex, time from the first transplant (&lt;12 months/ ≥12 months), conditioning intensity, sAHCT indication did not statistically significantly influence OS. Multivariate analysis confirmed a lower ECOG score (&lt;2) at sAHCT significantly increased OS (p= 0.001). Conclusions: Based on this single center study, sAHCT is an efficacious treatment modality especially for patients with lower ECOG scores. sAHCT may offer long term survival for both graft failure and disease relapse states.